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Xin-Long Yan,
Ya-Li Jia,
Lin Chen,
Quan Zeng,
Jun-Nian Zhou,
Chun-Jiang Fu,
Hai-Xu Chen,
Hong-Feng Yuan,
Zhi-Wei Li,
Lei Shi,
Ying-Chen Xu,
Jing-Xue Wang,
Xiao-Mei Zhang,
Li-Juan He,
Chao Zhai,
Wen Yue,
Xue-Tao Pei
[show abstract]
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ABSTRACT: Recent evidence indicates that cancer-associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer-associated MSCs (LC-MSCs) and hepatocellular carcinoma (HCC) remain unreported. Here, for the first time, we identified the presence of MSCs in HCC tissues. We also showed that LC-MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC-MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. cDNA microarray analysis showed that S100A4 expression was significantly higher in LC-MSCs compared with liver normal MSCs (LN-MSCs) from adjacent cancer-free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC-MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic miR-155 in HCC cells was significantly up-regulated by co-culture with LC-MSCs and by S100A4 ectopic overexpression. The invasion-promoting effects of S100A4 were significantly attenuated by a miR-155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR-155 expression in HCC cells. We demonstrate that S100A4 secreted from LC-MSCs promotes the expression of miR-155, which mediates the downregulation of suppressor of cytokine signaling 1 (SOCS1), leading to the subsequent activation of STAT3 signaling. This promotes the expression of MMP9, which results in increased tumor invasiveness. Conclusion: Our study reveals that S100A4 secreted from LC-MSCs, is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013.).
Hepatology 01/2013; · 11.66 Impact Factor
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Jing-Xue Wang,
Quan Zeng,
Lin Chen,
Ji-Chao Du, Xin-Long Yan,
Hong-Feng Yuan,
Chao Zhai,
Jun-Nian Zhou,
Ya-Li Jia,
Wen Yue,
Xue-Tao Pei
[show abstract]
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ABSTRACT: SPINDLIN1, a new member of the SPIN/SSTY gene family, was first identified as a gene highly expressed in ovarian cancer cells. We have previously shown that it is involved in the process of spindle organization and chromosomal stability and plays a role in the development of cancer. Nevertheless, the mechanisms underlying its oncogenic role are still largely unknown. Here, we first showed that expression of SPINDLIN1 is upregulated in clinical tumors. Ectopic expression of SPINDLIN1 promoted cancer cell proliferation and activated WNT/T-cell factor (TCF)-4 signaling. The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function. Collectively, these results suggest that SPINDLIN1, which may be a novel substrate of the Aurora-A kinase, promotes cancer cell growth through WNT/TCF-4 signaling activation.
Molecular Cancer Research 02/2012; 10(3):326-35. · 4.29 Impact Factor
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Ya-Li Jia,
Lei Shi,
Jun-Nian Zhou,
Chun-Jiang Fu,
Lin Chen,
Hong-Feng Yuan,
Yun-Fang Wang, Xin-Long Yan,
Ying-Chen Xu,
Quan Zeng,
Wen Yue,
Xue-Tao Pei
[show abstract]
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ABSTRACT: The high incidence rate of hepatocellular carcinoma (HCC) is mainly the result of frequent metastasis and tumor recurrence. Unfortunately, the underlying molecular mechanisms driving HCC metastasis are still not fully understood. It has been demonstrated that tumor stroma cells contribute to primary tumor growth and metastasis. Within the HCC environment, activated hepatic stellate cells (HSCs) can release a number of molecules and enhance cancer cell proliferation and invasiveness in a paracrine manner. Here, for the first time, we demonstrate that epimorphin (EPM; also called syntaxin-2), an extracellular protein, is strongly elevated in activated HSCs within tumor stroma. We show that knockdown of EPM expression in HSCs substantially abolishes their effects on cancer cell invasion and metastasis. Ectopic expression of EPM in HCC cancer cells enhances their invasiveness; we demonstrate that the cells expressing EPM have markedly increased metastasis potential. Furthermore, EPM-mediated invasion and metastasis of cancer cells is found to require up-regulation of matrix metalloproteinase-9 (MMP-9) through the activation of focal adhesion kinase (FAK)/extracellular signal-regulated kinase (ERK) axis. CONCLUSION: Our results show that EPM, secreted by activated HSCs within HCC stroma, promotes invasion and metastasis of cancer cells by activating MMP-9 expression through the FAK-ERK pathway.
Hepatology 11/2011; 54(5):1808-18. · 11.66 Impact Factor
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Hong-Feng Yuan,
Chao Zhai, Xin-Long Yan,
Dan-Dan Zhao,
Jing-Xue Wang,
Quan Zeng,
Lin Chen,
Xue Nan,
Li-Juan He,
Si-Ting Li,
Wen Yue,
Xue-Tao Pei
[show abstract]
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ABSTRACT: Human mesenchymal stem cells (MSCs) have therapeutic potential because of their ability to self-renew and differentiate into multiple tissues. However, senescence often occurs in MSCs when they are cultured in vitro and the molecular mechanisms underlying this effect remain unclear. In this study, we found that NAD-dependent protein deacetylase SIRT1 is differentially expressed in both human bone marrow-derived MSCs (B-MSCs) and adipose tissue-derived MSCs after increasing passages of cell culture. Using lentiviral shRNA we demonstrated that selective knockdown of SIRT1 in human MSCs at early passage slows down cell growth and accelerates cellular senescence. Conversely, overexpression of SIRT1 delays senescence in B-MSCs that have undergone prolonged in vitro culturing and the cells do not lose adipogenic and osteogenic potential. In addition, we found that the delayed accumulation of the protein p16 is involved in the effect of SIRT1. However, resveratrol, which has been used as an activator of SIRT1 deacetylase activity, only transiently promotes proliferation of B-MSCs. Our findings will help us understand the role of SIRT1 in the aging of normal diploid cells and may contribute to the prevention of human MSCs senescence thus benefiting MSCs-based tissue engineering and therapies.
Journal of Molecular Medicine 10/2011; 90(4):389-400. · 4.67 Impact Factor
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Xin-long Yan,
Chun-jiang Fu,
Lin Chen,
Jin-hua Qin,
Quan Zeng,
Hong-feng Yuan,
Xue Nan,
Hai-xu Chen,
Jun-nian Zhou,
Yan-li Lin,
Xiao-mei Zhang,
Cheng-ze Yu,
Wen Yue,
Xue-tao Pei
[show abstract]
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ABSTRACT: Mesenchymal stem cells (MSCs) play a critical role in promoting cancer progression. However, it is not clear whether MSCs are located in breast cancer tissues and correlated with tumor proliferation. The aim of this study was to investigate the presence of MSCs in breast cancer tissues and evaluate their interactions with cancer cells. We successfully isolated and identified MSCs from primary breast cancer tissues. Breast cancer-associated MSCs (BC-MSCs) showed homogenous immunophenotype, and possessed tri-lineage differentiation potential (osteoblast, adipocyte, and chondrocyte). When co-transplanted with cancer cells in a xenograft model in vivo, BC-MSCs significantly increased the volume and weight of tumors. We observed that BC-MSCs stimulated mammosphere formation in the transwell co-culture system in vitro. This effect was significantly suppressed by the EGF receptor inhibitor. We verified that BC-MSCs could secrete EGF and activate cancer cell's EGF receptors. Furthermore, our data showed that EGF derived from BC-MSCs could promote mammosphere formation via the PI3K/Akt signaling pathway. Our results confirmed the presence of MSC in primary breast cancer tissues, and they could provide a favorable microenvironment for tumor cell growth in vivo, partially enhance mammosphere formation via the EGF/EGFR/Akt pathway.
Breast Cancer Research and Treatment 05/2011; 132(1):153-64. · 4.43 Impact Factor
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Xin-Long Yan,
Yu Lan,
Xiao-Yan Wang,
Wen-Yan He,
Hui-Yu Yao,
Dong-Bo Chen,
Jia-Xiang Xiong,
Jiao Gao,
Zhuan Li,
Guan Yang,
Xiu-Sen Li,
Yuan-Lin Liu,
Ji-Yan Zhang,
Bing Liu,
Ning Mao
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ABSTRACT: Mesenchymal stem cells (MSCs) represent powerful tools for regenerative medicine for their differentiation and migration capacity. However, ontogeny and migration of MSCs in mammalian mid-gestation conceptus is poorly understood. We identified canonical MSCs in the mouse embryonic day (E) 11.5 dorsal aorta (DA). They possessed homogenous immunophenotype (CD45(-)CD31(-)Flk-1(-)CD44(+)CD29(+)), expressed perivascular markers (α-SMA(+)NG2(+)PDGFRβ(+)PDGFRα(+)), and had tri-lineage differentiation potential (osteoblasts, adipocytes, and chondrocytes). Of interest, MSCs were also detected in E12.5-E13.5 embryonic circulation, 24 hr later than in DA, suggesting migration like hematopoietic stem cells. Functionally, E12.5 embryonic blood could trigger efficient migration of DA-MSCs through platelet-derived growth factor (PDGF) receptor-, transforming growth factor-beta receptor-, but not basic fibroblast growth factor receptor-mediated signaling. Moreover, downstream JNK and AKT signaling pathway played important roles in embryonic blood- or PDGF-mediated migration of DA-derived MSCs. Taken together, these results revealed that clonal MSCs developed in the mouse DA. More importantly, the embryonic circulation, in addition to its conventional transporting roles, could modulate migration of MSC during early embryogenesis.
Developmental Dynamics 01/2011; 240(1):65-74. · 2.54 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) are multipotent stem cells capable of differentiating into various cell types, including osteocytes, chondrocytes, adipocytes, myocytes, and tenocytes. However, the difficulty or failure in expanding the mouse MSCs in vitro greatly hampered important research in animal models. The OP9, a stromal cell line from mouse bone marrow, has hematopoietic supportive capacity. Here, we report that the OP9 has the immunophenotype (CD45(-), CD11b(-), FLK-1(-), CD31(-), CD34(-), CD44(+), CD29(+), Sca-1(+), CD86(-), and MHCII(-)) identical to canonical mouse MSCs. The expression of CD140a(+), CD140b(+), alpha-SMA(+) and Calponin(+) suggested the perivascular origin of OP9. Functionally, the OP9 had strong clonogenic ability and could be induced into osteocytes, chondrocytes and adipocytes. The lymphocyte transformation test (LTT) and mixed leukocyte reaction (MLR) showed that the OP9 could suppress T lymphocyte proliferation stimulated by nonspecific mitogens (PHA) or allogeneic lymphocytes (BALB/c T cells). Finally, the migration of OP9 could be efficiently induced by bFGF, IGF-1, IL-3, PDGF-BB, TGF-beta1 and TGF-beta3. In conclusion, the OP9 were bona fide MSCs, and such homogenous cell line will be helpful to delineate biological features of MSCs at the stem cell level.
Journal of Genetics and Genomics 07/2010; 37(7):475-82. · 1.88 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSCs) are multipotent stem cells which can support hematopoiesis, have immunomodulatory property, may differentiate into osteocytes, chondrocytes and adipocytes, and specifically migrate to damage sites and tumor site, but the mechanism involved in the regulation of migration of MSCs still remains unelucidated. Understanding the fundamental mechanisms underlying MSCs migration holds the promise of developing novel clinical strategies which can deliver antitumor proteins to suppress tumor growth. In this review, the MSC migration in vitro mediated by growth factors, chemokines, adhesion molecules and toll-like receptors are summarized.
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 09/2009; 17(4):1101-5.
